Mechanistic evaluation of Th2-polarizing bystander effects of early life immunization with alum

生命早期明矾免疫Th2极化旁观者效应的机制评估

• 批准号: 10312801
• 负责人: Jessica Jane O'Konek
• 金额: $ 19.5万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-15 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10312801
• 关键词: Achievement; Address; Adjuvant; Adult; Affect; Age; Agonist; Allergic; Allergic Disease; Allergic Reaction; Aluminum; Antigens; Birth; Bone Marrow; Bystander Effect; Child; Data; Development; Evaluation; Exposure to; Health; Health Benefit; Hepatitis B Vaccines; Human; Immune; Immune System Diseases; Immune Targeting; Immune response; Immune system; Immunity; Immunization; Immunize; Immunologic Adjuvants; Infant; Inhalation Exposure; Instruction; Investigation; Knowledge; Lead; Life; Lymphoid Cell; Maintenance; Modification; Mus; Neonatal; Oral; Ovum; Pathology; Predisposition; Preventative vaccination; Property; Public Health; Route; Safety; Schedule; Signal Transduction; Squalene; Stimulus; TLR4 gene; Testing; Time; United States; Vaccination; Vaccine Adjuvant; Vaccine Design; Vaccines; Virus; Work; age effect; base; design; imprint; improved; infancy; microbiota; neonatal immune system; neonate; novel; novel vaccines; prevent; response; vaccine development; vaccine safety

PROJECT SUMMARY Prophylactic immunization has substantially improved human health. While vaccines have been a major achievement in advancing human health, adjuvant options for vaccines are extremely limited. While alum-based adjuvants are the main immunostimulants used in vaccines, the mechanisms of action remain poorly understood, especially relating to the long-lasting immune effects on the immature neonatal and infant immune system. Until now, the focus on mechanism of action of alum has centered around antigen-specific effects in boosting immunity to the immunogen delivered with alum. Our preliminary data demonstrate that immunization of 21 day old mice with hepatits B virus (HB) alum vaccine alters the response to subsequent inhalation exposure to newly introduced immunogens. Mice that had not been previously immunized with the alum-based vaccine developed tolerogenic immune responses to the novel immunogen. Alternatively, mice that received the alum vaccine were predisposed to developing Th2-polarized immune responses to the novel immunogen which led to allergic reactions to challenge. Here, we aim to determine the contribution of alum-driven bystander effects on immune responses to newly introduced immunogens. This proposal is designed to generate proof-of-concept that early life immunization with alum results in Th2 imprinting that does not occur following alum immunization later in life. We propose to test our hypothesis that early life immunization with alum prolongs the Th2-bias of the neonatal immune system by 1) determining the impact of age at the time of alum immunization on maintenance of a Th2- biased immune system and 2) defining the mechanism by which immunization with the HB-alum vaccine modulates immune responses to subsequently introduced immunogens. Thus, furthering our understanding of how early life immunization with alum-based vaccines maintain a Th2-biased immune system is important for rational vaccine design as well as implementation of vaccine schedules. This is especially important to understand as infants receiving many vaccines which contain alum, including the HB vaccine which is given at birth. Definition of the mechanisms of action of adjuvants in early-life compared to later in life may lead to the development of age-specific adjuvants in order to maintain the public health benefit of vaccination while reducing broad effects on the immune system that may lead to immune pathologies later in life.

项目概要 预防性免疫极大地改善了人类健康。虽然疫苗一直是主要 尽管在促进人类健康方面取得了成就，但疫苗佐剂的选择极其有限。虽然以明矾为基础 佐剂是疫苗中使用的主要免疫刺激剂，其作用机制仍知之甚少， 尤其是对未成熟的新生儿和婴儿免疫系统的长期免疫影响。直到 现在，对明矾作用机制的关注点集中在增强免疫力方面的抗原特异性作用 与明矾一起递送的免疫原。我们的初步数据表明，21 日龄小鼠的免疫接种 乙型肝炎病毒 (HB) 明矾疫苗改变了对随后吸入暴露于新病毒的反应 引入免疫原。之前未曾接种过基于明矾的疫苗的小鼠被开发出来 对新型免疫原的耐受性免疫反应。或者，接受明矾疫苗的小鼠 倾向于对新型免疫原产生 Th2 极化免疫反应，从而导致过敏 对挑战的反应。在这里，我们的目标是确定明矾驱动的旁观者效应对免疫的贡献 对新引入的免疫原的反应。该提案旨在尽早生成概念验证 一生中使用明矾进行免疫会导致 Th2 印记，而在以后的生活中进行明矾免疫后不会出现这种印记。 我们建议检验我们的假设，即早期使用明矾进行免疫可延长新生儿的 Th2 偏向性。 免疫系统通过 1) 确定明矾免疫时年龄对维持 Th2- 的影响 偏向免疫系统和 2) 定义 HB-明矾疫苗免疫的机制 调节对随后引入的免疫原的免疫反应。从而加深我们对 生命早期使用明矾疫苗进行免疫如何维持偏向 Th2 的免疫系统对于 合理的疫苗设计以及疫苗接种计划的实施。这对于 据了解，婴儿接受了许多含有明矾的疫苗，包括 HB 疫苗。 出生。佐剂在生命早期和生命后期的作用机制的定义可能会导致 开发针对特定年龄的佐剂，以维持疫苗接种的公共卫生益处，同时减少 对免疫系统产生广泛影响，可能导致晚年出现免疫病变。